The research is at present focused on the relative roles of metabolic activation and detoxification in determining both mutagenic and carcinogenic potential of aromatic amines and amides. Results so far obtained include: (1) Two distinct phenotypes, slow and fast metabolizers, were observed for both metabollic activation and detoxification of the model chemical carcinogen, 2-acetylaminofluorene, in human liver microsomes from 28 individuals. We observed that individuals who were fast activators of the carcinogen were, in most cases, also fast detoxifiers of the chemical. However, different phenotype patterns exist suggesting that fast activators of a toxin need not also be phenotyped as fast detoxifiers. Studies in this areas may help understand whether certain individuals are predisposed to a higher rate of chemically-induced cancers. (2) The kinetics of cytochrome P-450 dependent N-hydroxylation of 2-aminofluorene (AF) and 4-aminobiphenyl (4-AB) were determined using six highly purified forms of rabbit cytochrome P-450 and microsomes from control and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induced rabbit liver and lung. N-Hydroxylation of both AF and 4-AF was best defined by two enzyme systems, showing a high affinity low capacity and a low affinity high capacity, in control and TCDD microsomes. Pretreatment of TCDD modified the apparent Km and Vmax for the N-hydroxylation of both substrates in liver and lung microsomes, but the biphasic kinetics were observed in all instances. Form 4 was the only form capable of catalyzing the N-hydroxylation of AF and 4-AB. The kinetic data obtained with form 4 for these two substrates were consistent with a single enzyme sytem. Alpha-Naphthoflavone (ANF) completely inhibited the N-hydroxylation of AF in liver microsomes from both control and TCDD treated animals, whereas only partial inhibition was obtained with lung microsomes. These results indicate that at least two forms of cytochrome P-450 with greatly different substrate affinity (Km) participate in the N-hydroxylation of primary aromatic amines in rabbit liver and lung microsomes.